Viscoelastic haemostatic point-of-care assays in the management of postpartum haemorrhage: a narrative review.

Viscoelastic haemostatic assays provide rapid testing at the bed-side that identify all phases of haemostasis, from initial fibrin formation to clot lysis. In obstetric patients, altered haemostasis is common as pregnancy is associated with coagulation changes that may contribute to bleeding events such as postpartum haemorrhage, as well as thrombosis events. In this narrative review, we examine the potential clinical utility of viscoelastic haemostatic assays in postpartum haemorrhage and consider the current recommendations for their use in obstetric patients. We discuss the clinical benefits associated with the use of viscoelastic haemostatic assays due to the provision of (near) real-time readouts with a short turnaround, coupled with the identification of coagulation defects such as hypofibrinogenaemia. The use of viscoelastic haemostatic assay-guided algorithms may be beneficial to diagnose coagulopathy, predict postpartum haemorrhage, reduce transfusion requirements and monitor fibrinolysis in women with obstetric haemorrhage. Further studies are required to assess whether viscoelastic haemostatic assay-guided treatment improves clinical outcomes, and to confirm the utility of prepartum viscoelastic haemostatic assay measurements for identifying patients at risk of postpartum haemorrhage.

Separation of hemodynamic signals from GCaMP fluorescence measured with wide-field imaging.

Wide-field calcium imaging is often used to measure brain dynamics in behaving mice. With a large field of view and a high sampling rate, wide-field imaging can monitor activity from several distant cortical areas simultaneously, revealing cortical interactions. Interpretation of wide-field images is complicated, however, by the absorption of light by hemoglobin, which can substantially affect the measured fluorescence. One approach to separating hemodynamics and calcium signals is to use multiwavelength backscatter recordings to measure light absorption by hemoglobin. Following this approach, we develop a spatially detailed regression-based method to estimate hemodynamics. This Spatial Model is based on a linear form of the Beer-Lambert relationship but is fit at every pixel in the image and does not rely on the estimation of physical parameters. In awake mice of three transgenic lines, the Spatial Model offers improved separation of hemodynamics and changes in GCaMP fluorescence. The improvement is pronounced near blood vessels and, in contrast with the Beer-Lambert equations, can remove vascular artifacts along the sagittal midline and in general permits more accurate fluorescence-based determination of neuronal activity across the cortex.NEW & NOTEWORTHY This paper addresses a well-known and strong source of contamination in wide-field calcium-imaging data: hemodynamics. To guide researchers toward the best method to separate calcium signals from hemodynamics, we compare the performance of several methods in three commonly used mouse lines and present a novel regression model that outperforms the other techniques we consider.

A New Realization of SI for Organic Chemical Measurement: NIST PS1 Primary Standard for Quantitative NMR (Benzoic Acid).

Metrological traceability to common references supports the comparability of chemical measurement results produced by different analysts, at various times, and at separate places. Ideally, these references are realizations of base units of the International System of Units (SI). ISO/IEC 17025 (Clause 6.5) states that traceability of measurement results is a necessary attribute of analytical laboratory competence, and as such, has become compulsory in many industries, especially clinical diagnostics and healthcare. Historically, claims of traceability for organic chemical measurements have relied on calibration chains anchored on unique reference materials with linkage to the SI that is tenuous at best. A first-of-its-kind National Institute of Standards and Technology (NIST) reference material, ultrapure and extensively characterized PS1 Benzoic Acid Primary Standard for quantitative NMR (qNMR), serves as a definitive, primary reference (calibrant) that assuredly links the qNMR spectroscopy technique to SI units. As qNMR itself is a favorable method for accurate, direct characterization of chemical reference materials, PS1 is a standard for developing other traceable standards and is intended to establish traceability for the measurement of thousands of organic chemical species. NIST PS1 will play a critical role in directly promoting accuracy and worldwide comparability of measurement results produced by the chemical measurement community, supporting the soundness of clinical diagnostics, food safety and labeling, forensic investigation, drug development, biomedical research, and chemical manufacturing. Confidence in this link to the SI was established through (i) unambiguous identification of chemical structure; (ii) determinations of isotopic composition and molecular weight; (iii) evaluation of the respective molecular amount by multiple primary measurement procedures, including qNMR and coulometry; and (iv) rigorous evaluation of measurement uncertainty using state-of-the-art statistical methods and measurement models.

Adult extracorporeal membrane oxygenation: an international survey of transfusion and anticoagulation techniques.

BACKGROUND AND OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) is a method of life support for either isolated cardiac failure or respiratory failure, with or without cardiac failure. When used for hemodynamic support, the ECMO circuit presents a non-endothelialized, artificial surface to blood inciting an inflammatory response which activates haemostatic pathways. Anticoagulation may complicate a pre-existing coagulopathy and/or inadequate surgical hemostasis of varying severity. There is no standardized method to achieve and monitor anticoagulation or guide transfusion therapy during ECMO. We tested the hypothesis that institutions across the world conduct similar management of anticoagulation and transfusion during adult ECMO support. METHODS: This is a descriptive, self-reporting cross-sectional survey of anticoagulation and transfusion practice for patients age 18 or older on ECMO. This 38 multiple-choice question survey was sent to 166 institutions, internationally, utilizing adult ECMO. About 32·4% (54) of institutions responded. Responses were anonymously collected. Descriptive analyses were calculated. RESULTS: Our findings indicate there appears to be a significant practice variation among institutions regarding anticoagulation and transfusion during adult ECMO support. DISCUSSION: The lack of standard practices among institutions may reflect a paucity of data regarding optimal anticoagulation and transfusion for patients requiring ECMO. Standardized protocols for anticoagulation and transfusion may help increase quality of care for and reduce morbidity, mortality and cost to patients and healthcare centres. Further study is required for standardized, high quality care.

Excessive quantities of red blood cells are issued to the operating room.

OBJECTIVES: To determine what percentage of red blood cell (RBC) units that were issued to the operating room (OR) were returned unused, and to determine how often all of the RBCs that were issued for a patient were returned unused using the institution's maximum surgical blood ordering schedule (MSBOS) as a guide. BACKGROUND: The MSBOS provides guidelines for blood ordering, but is merely a suggestion for the ordering clinicians. This study examined how closely ordering practices followed the MSBOS, and how often ordered RBCs were actually transfused. METHODS: For a 4-week period, RBC issue and utilization data were collected on elective surgery patients who were eligible for electronic cross-match at a tertiary care hospital. These data were compared to the MSBOS. RESULTS: There were 1350 surgical procedures performed. Of these cases, 439 patients had a type and screen (T&S) performed, and 215/439 (49%) patients had at least 1 RBC issued during their case. To these 215 patients, 742 RBC units were issued and 537/742 (72%) of these units were returned to the blood bank unused. In 152/215 (71%) cases with issued RBCs, all of the RBCs were returned to the blood bank unused. Amongst the surgical categories in this study, the percentage of cases where none of the issued RBCs were transfused ranged from 38 to 93%. CONCLUSIONS: Significant numbers of RBC units are issued but not transfused during surgery. Involving the surgical team in the blood issuing process and using a data-driven MSBOS may reduce the number of unused units.

Investigating the widely held belief that men and women with learning disabilities receive poor quality healthcare when admitted to hospital: a single-site study of 30-day readmission rates.

BACKGROUND: This study aims to use 30-day readmission rates to investigate the presumption that men and women with learning disabilities (LDs, known internationally as intellectual disabilities) receive poorer quality hospital care than their non-disabled peers. METHOD: A 12-month retrospective audit was conducted using Hospital Episode Statistics (HES) at a single acute hospital in the East of England. This identified all in-patient admissions; admissions where the person concerned was recognised as having a LD; and all emergency readmissions within 30 days of discharge. Additionally, the healthcare records of all patients identified as having a LD and readmitted within 30 days as a medical emergency were examined in order to determine whether or not these readmissions were potentially preventable. RESULTS: Over the study period, a total of 66 870 adults were admitted as in-patients, among whom 7408 were readmitted as medical emergencies within 30 days of discharge: a readmission rate of 11%. Of these 66 870 patients, 256 were identified as having a LD, with 32 of them experiencing at least one emergency readmission within 30 days: a readmission rate of 13%. When examined, the healthcare records pertaining to these 32 patients who had a total of 39 unique 30-day readmissions revealed that 69% (n = 26) of these readmissions were potentially preventable. CONCLUSION: Although overall readmission rates were similar for patients with LDs and those from the general population, patients with LDs had a much higher rate of potentially preventable readmissions when compared to a general population estimate from van Walraven et al. This suggests that there is still work to be done to ensure that this patient population receives hospital care that is both safe and of high quality.

Role of the massive transfusion protocol in the management of haemorrhagic shock.

The concept of rapid delivery of multiple blood products to the bedside of a massively haemorrhaging patient seems to be a logical approach to the management of the massively bleeding patient. However, controversy exists in the use of fixed blood component ratios. Assessing the extent of the coagulopathy through point-of-care testing might provide patients with product administration as needed, and avoid excessive transfusion and its associated complications.

Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS: ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS: Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS: Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

In vitro self-assembly of human pericyte-supported endothelial microvessels in three-dimensional coculture: a simple model for interrogating endothelial-pericyte interactions.

We describe a method for coculture of macro- or microvascular human endothelial cells (ECs) and pericytes (PCs) within a 3-dimensional (3-D) protein matrix resulting in lumenized EC cords invested by PCs. To prevent apoptotic cell death of ECs in 3-D culture, human umbilical vein or dermal microvascular ECs were transduced to express the antiapoptotic protein Bcl-2. To prevent PC-mediated gel contraction, the collagen-fibronectin gel was polymerized within a polyglycolic acid nonwoven matrix. Over the first 24-48 h, EC-only gels spontaneously formed cords that developed lumens via vacuolization; such vascular networks were maintained for up to 7 days. In EC-PC cocultures, PCs were recruited to the EC networks. PC investment of EC cords both limited the lumen diameter and increased the degree of vascular network arborization. Peg and socket junctions formed between ECs and PCs in this system, but dye transfer, indicative of gap junction formation, was not observed. This simple system can be used to analyze bidirectional signals between ECs and PCs in a 3-D geometry.

Immediate post-operative brachytherapy prior to irradiation and temozolomide for newly diagnosed glioblastoma.

To determine whether immediate post-operative brachytherapy can be safely applied to newly diagnosed glioblastomas to retard tumor progression prior to initiation of external beam radiation therapy (EBRT) and temozolomide. Between 1996 and 2011, eleven patients underwent implantation of GliaSite (n = 9) or MammoSite (n = 2) at the time of surgical resection. Brachytherapy was carried out on post-operative day 2-3, with 45-60 Gy delivered to a 1 cm margin. All patients underwent subsequent standard radiation/temozolomide treatment 4-5 weeks post-irradiation. There were no wound related complications. Toxicity was observed in two patients (2/11 or 18 %), including one post-operative seizure and one case of cerebral edema that resolved after a course of steroid treatment. Immediate post-operative and pre-irradiation/temozolomide magnetic resonance imaging assessment was available for 9 of the 11 patients. Two of these nine patients (22 %) developed new regions of contrast enhancement prior to irradiation/temozolomide. This compares favorably to historical data where 53 % of patient suffer such tumor progression. While there was a trend toward improved 6 month progression free survival in the brachytherapy/temozolomide/radiation treated patients, the overall survival of these patients were comparable to historical controls. This case series demonstrates the safety of immediate post-operative brachytherapy when applied prior to EBRT and temozolomide in the treatment of newly diagnosed glioblastomas.

Swimming against the current: genetic structure, host mobility and the drift paradox in trematode parasites.

Life-cycle characteristics and habitat processes can potentially interact to determine gene flow and genetic structuring of parasitic species. In this comparative study, we analysed the genetic structure of two freshwater trematode species with different life histories using cytochrome c oxidase I gene (COI) sequences and examined the effect of a unidirectional river current on their genetic diversity at 10 sites along the river. We found moderate genetic structure consistent with an isolation-by-distance pattern among subpopulations of Coitocaecum parvum but not in Stegodexamene anguillae. These contrasting parasite population structures were consistent with the relative dispersal abilities of their most mobile hosts (i.e. their definitive hosts). Genetic diversity decreased, as a likely consequence of unidirectional river flow, with increasing distance upstream in C. parvum, which utilizes a definitive host with only restricted mobility. The absence of such a pattern in S. anguillae suggests that unidirectional river flow affects parasite species differently depending on the dispersal abilities of their most mobile host. In conclusion, genetic structure, genetic diversity loss and drift are stronger in parasites whose most mobile hosts have low dispersal abilities and small home ranges. An additional prediction can be made for parasites under unidirectional drift: those parasites that stay longer in their benthic intermediate host or have more than one benthic intermediate hosts would have relatively high local recruitment and hence increased retention of upstream genetic diversity.

CT322, a VEGFR-2 antagonist, demonstrates anti-glioma efficacy in orthotopic brain tumor model as a single agent or in combination with temozolomide and radiation therapy.

Glioblastomas are among the most aggressive human cancers, and prognosis remains poor despite presently available therapies. Angiogenesis is a hallmark of glioblastoma, and the resultant vascularity is associated with poor prognosis. The proteins that mediate angiogenesis, including vascular endothelial growth factor (VEGF) signaling proteins, have emerged as attractive targets for therapeutic development. Since VEGF receptor-2 (VEGFR-2) is thought to be the primary receptor mediating angiogenesis, direct inhibition of this receptor may produce an ideal therapeutic effect. In this context, we tested the therapeutic effect of CT322, a selective inhibitor of VEGFR-2. Using an intracranial murine xenograft model (U87-EGFRvIII-luciferase), we demonstrate that CT322 inhibited glioblastoma growth in vivo and prolonged survival. Of note, the anti-neoplastic effect of CT322 is augmented by the incorporation of temozolomide or temozolomide with radiation therapy. Immunohistochemical analysis of CT322 treated tumors revealed decreased CD31 staining, suggesting that the tumoricidal effect is mediated by inhibition of angiogenesis. These pre-clinical results provide the foundation to further understand long term response and tumor escape mechanisms to anti-angiogenic treatments on EGFR over-expressing glioblastomas.

Haemolysis and sublethal injury of RBCs after routine blood bank manipulations.

OBJECTIVES: To determine the extent of RBC sublethal injury in male donor units as measured by both the mechanical fragility index (MFI) and percentage haemolysis after RBCs underwent leucoreduction (LR), irradiation (IRRAD), and washing. BACKGROUND: RBCs frequently undergo post-collection processing to meet certain recipient's special needs. The extent of haemolysis and sublethal injury following these interventions has not been fully characterised. METHODS: Eight to ten day old male, AS-5 RBCs underwent either LR, IRRAD or washing. A control group of male, AS-5 RBCs were unmanipulated. The MFI, percent haemolysis, and plasma free haemoglobin (PFHb) were measured immediately after manipulation and, for a series of irradiated RBCs, 28 days after irradiation (IRRAD28). RESULTS: The MFI of the washed units was significantly higher than unmanipulated, LR, IRRAD, IRRAD28 units (P < 0·0001). The percent haemolysis was highest in the IRRAD28 units (1·4%) followed by the washed units (0·74%); the other three units demonstrated significantly less haemolysis (P < 0·0001). The largest mean total amount of PFHb per unit was found in the IRRAD28 units (500·5 mg/unit) followed by the washed units (149·8 mg/unit); the mean total amount of PFHb in the three other types of units was significantly less than that found in both the IRRAD28 and washed units (P at least < 0·001). CONCLUSION: There is a significant quantity of PFHb in IRRAD28 RBC units, and potentially in washed allogeneic RBC units. Clinical correlation is required to determine if this quantity of PFHb and the transfusion of potentially fragile RBCs causes adverse events.

Malignancies of the spinal cord.

The management of intramedullary spinal cord tumors (IMSCT) is primarily concerned with the preservation of existing neurologic function. To this end, clinical scientists are continually seeking tools and techniques to improve the safety and efficacy of tumor resection and control. Further advances in safety and efficacy can be proposed at each phase of management, from pre-operative screening to post-treatment monitoring. Innovations within the areas of molecular biology and genetics, intraoperative imaging and stereotactic radiosurgery offer exciting new options to explore in the management of IMSCT. This section will review the pathophysiology and epidemiology of IMSCT and the state-of-the-art management before delving into the promising new tools and techniques for each phase of management.

A Perspective on Substorm Dynamics Using 10 Years of Auroral Kilometric Radiation Observations From Wind.

We study 10 years (1995-2004 inclusive) of auroral kilometric radiation (AKR) radio emission data from the Wind spacecraft to examine the link between AKR and terrestrial substorms. We use substorm lists based on parameters including ground magnetometer signatures and geosynchronous particle injections as a basis for superposed epoch analyses of the AKR data. The results for each list show a similar, clear response of the AKR power around substorm onset. For nearly all event lists, the average response shows that the AKR power begins to increase around 20 min prior to expansion phase onset, as defined by the respective lists. The analysis of the spectral parameters of AKR bursts show that this increase in power is due to an extension of the source region to higher altitudes, which also precedes expansion phase onset by 20 min. Our observations show that the minimum frequency channel that observes AKR at this time, on average, is 60 kHz. AKR visibility is highly sensitive to observing spacecraft location, and the biggest radio response to substorm onset is seen in the 21:00-03:00 hr local time sector.

Evolutionary consequences of microhabitat: population-genetic structuring in kelp- vs. rock-associated chitons.

Rafting has long been invoked as a key marine dispersal mechanism, but biologists have thus far produced little genetic evidence to support this hypothesis. We hypothesize that coastal species associated with buoyant seaweeds should experience enhanced population connectivity owing to rafting. In particular, invertebrates strongly associated with the buoyant bull-kelp Durvillaea antarctica might be expected to have lower levels of population-genetic differentiation than taxa mainly exploiting nonbuoyant substrates. We undertook a comparative genetic study of two codistributed, congeneric chiton species, assessing population connectivity at scales of 61-516 km, using ≥ 186 polymorphic AFLP loci per species. Consistent with predictions, population-genetic differentiation was weaker in the kelp-associated Sypharochiton sinclairi than in the rock-associated S. pelliserpentis. Additionally, while we found a significant positive correlation between genetic and oceanographic distances in both chiton species, the correlation was stronger in S. pelliserpentis (R(2) = 0.28) than in S. sinclairi (R(2) = 0.18). These data support the hypothesis that epifaunal taxa can experience enhanced population-genetic connectivity as a result of their rafting ability.

Pathways of spindle assembly.

Recent studies have revealed that, in some systems, chromatin has the ability to stabilize microtubules and organize them into bipolar spindles independently of kinetochores and centrosomes. In addition, several molecules have been identified recently that are necessary for spindle assembly; these include proteins that regulate microtubule dynamics, proteins that organize microtubule minus ends into spindle poles, and members of the kinesin superfamily that reside on the chromosome arms.

Menopausal status affects the susceptibility of stored RBCs to mechanical stress.

The mechanical fragility index (MFI) is an in vitro measure of sublethal injury to RBCs. In our previous experiments, we demonstrated that an increase in sublethal injury (increasing MFI) was a component of the RBC storage lesion, and that the MFI was significantly higher amongst the RBC units from male donors compared to pre-menopausal female donors during storage. It was hypothesized that hormonal or menstrual factors contributed to this difference. In this study, we found that RBC units donated by post-menopausal women demonstrated an MFI that was significantly higher than those donated by pre-menopausal women throughout storage.

When and how should I transfuse during obstetric hemorrhage?

The incidence of maternal hemorrhage and blood transfusion has increased over time. Causes of massive hemorrhage, defined as a transfusion > 10 units of erythrocytes, include abnormal placental insertion, preeclampsia, and placental abruption. Although ratio-based transfusion has been described for managing massive hemorrhage, a goal-directed approach using laboratory or point-of-care data may lead to better outcomes. Autotransfusion, which involves the collection, washing, and filtration of maternal shed blood, avoids many of the complications associated with allogeneic blood transfusion. In this review, we provide an overview of transfusion practices related to the management of obstetric hemorrhage.